Hepatitis A Among Persons with Hemophilia Who Received
Clotting Factor Concentrate -- United States, September-December 199

Hepatitis A outbreaks associated with receipt of clotting
factor
concentrate previously have been recognized in Europe but not in
the United
States (1-5). During September-November 1995, three cases of
hepatitis A in
recipients of Alphanate (TM) * factor VIII concentrate (Alpha
Therapeutic
Corporation, Los Angeles, California) from lot number AP5014A were
reported
to CDC. On December 8, the manufacturer voluntarily withdrew
Alphanate (TM)
lot number AP5014A from the market. In addition, one case of
hepatitis A in
a recipient of AlphaNine S-D (TM) factor IX concentrate (Alpha
Therapeutic
Corporation) has been reported and is under investigation. On
January 11,
1996, the manufacturer voluntarily withheld four lots of AlphaNine
S-D (TM)
from further distribution as a precautionary measure. This report
describes
these four cases, summarizes the status of the investigation of the
cases,
and provides guidelines for testing and reporting of patients who
received
these products.

Hepatitis A in Factor VIII Recipients

Case 1. On September 5, 1995, a 13-year-old boy with mild
hemophilia A
(factor VIII deficiency) became acutely ill with nausea and
vomiting after
a 2-week period of fatigue, poor appetite, and low-grade fever.
Blood tests
revealed elevated liver enzymes and a positive test for
immunoglobulin M
antibody to hepatitis A virus (IgM anti-HAV). No sources of
infection
(e.g., close contact with a person with hepatitis A, household
contact with
a person working in or attending a day-care center, or
international
travel) were reported. During the 6 weeks preceding illness, the
patient
had used 68 vials (approximately 34,000 units) from the implicated
lot
(i.e., lot number AP5014A) of Alphanate (TM) and nine vials from
four lots
of another brand of factor VIII concentrate.

Case 2. On October 20, during a hospital visit to evaluate
vaginal
bleeding 1 month postpartum, a 28-year-old woman with type 2 von
Willebrand
disease was found to have elevated liver enzymes and was IgM
anti-HAV
positive. She reported that, during September, she had had dinner
on two
occasions with an international visitor who had appeared jaundiced
but not
ill. No other potential sources of infection were identified.
During 1995,
her only exposure to factor concentrate was use of 48 vials
(approximately
24,000 units) of Alphanate (TM) from the implicated lot on
September 19.

Case 3. On November 10, the National Hemophilia Foundation
faxed a
medical bulletin nationwide to 140 hemophilia treatment centers
describing
the first two cases of hepatitis A and their possible association
with
Alphanate (TM) lot number AP5014A. In response to this bulletin,
two
brothers with hemophilia A (aged 6 and 7 years) who had received
this
clotting factor concentrate were identified and tested for anti-HAV
on
November 17. The younger boy was IgM anti-HAV positive; the older
boy was
anti-HAV positive and IgM anti-HAV negative. Three weeks before
testing for
IgM anti-HAV, the younger brother had had a 5-day illness with
nausea,
vomiting, and abdominal pain. During the 3 months preceding
testing, both
boys had received approximately equal amounts of a total of 31
vials
(approximately 15,500 units) of Alphanate (TM) from the implicated
lot. No
other factor products had been used during this interval, and no
other
sources of infection were identified.

Laboratory studies. One sample each from the implicated lot of
Alphanate (TM), acute-phase serum from patient 2, and stool from
patient 1
were positive for HAV RNA after amplification by polymerase chain
reaction
of the amino terminal region of that portion of the HAV genome
coding for
VP1. Genetic sequencing indicated that the viral nucleic acid
isolated from
each source was of HAV genotype 1a. Sequence analysis indicated
that these
isolates were identical and unique from other previously sequenced
strains
(6).

Hepatitis A in a Factor IX Recipient

On December 7, 1995, a 15-year-old boy with severe hemophilia
B
(factor IX deficiency) presented to his physician with symptoms of
acute
hepatitis; diagnostic studies indicated elevated liver enzymes and
a
positive test for IgM anti-HAV. No sources of infection were
identified,
and his family members were negative for anti-HAV and IgM anti-HAV.
During
the 3 months preceding testing, the boy had received 40 vials
(approximately 40,000 units) of AlphaNine S-D (TM); most of the
vials had
come from four different product lots. Three of these lots
originated from
source plasma pools common to the implicated lot of Alphanate (TM).

Editorial Note

Editorial Note: This report is the first to document transmission
of HAV
through clotting factor concentrates in the United States. Most
cases of
hepatitis A in the United States occur in community-wide outbreaks
through
person-to-person transmission by the fecal-oral route. However,
because
viremia occurs during the prodromal phase of the illness,
asymptomatic
blood donors, on rare occasions, have been the source of HAV
infection
transmitted by transfusion (7).

Several key findings support the conclusion that clotting
factor
concentrate was the source of infection in the factor VIII
case-patients.
First, the cases occurred in geographically dispersed areas, none
of which
were having community-wide epidemics of hepatitis A, and no
community
source of infection was identified. Second, the patients received
the same
lot of factor VIII concentrate. Third, HAV RNA was identified in
that
product lot. Finally, the genetic sequence of the HAV RNA from the
factor
concentrate was identical to that obtained from two of the
case-patients.

In Europe, investigations of recent hepatitis A outbreaks
among
recipients of factor VIII concentrates implicated products prepared
by a
manufacturing method that included a solvent detergent (S-D) viral
inactivation step (1-5). The largest outbreak occurred in Italy,
involving
52 patients with hemophilia (5). The only risk factor for hepatitis
A
infection was receipt of factor VIII concentrate prepared using
this
method, and HAV RNA was detected in the factor concentrate (8). No
hepatitis A outbreaks associated with receipt of factor IX
concentrates
have been reported previously.

The factor concentrates used by the case-patients described in
this
report also were prepared using the S-D method of viral
inactivation.
Although this method inactivates enveloped viruses such as
hepatitis B
virus, hepatitis C virus, and human immunodeficiency virus (9),
nonenveloped viruses such as HAV are resistant to inactivation by
this
method. Other plasma-derived factor VIII and factor IX concentrates
manufactured using similar or different viral-reducing steps also
may
contain HAV, although no documented cases of transmission have been
reported. Clotting factor concentrates manufactured by recombinant
technology, which are now available for the treatment of factor
VIII
deficiency, have not been shown to transmit infectious agents. No
recombinant factor IX clotting products have been approved by the
Food and
Drug Administration.

CDC is continuing to investigate these cases and requests
assistance
in identifying additional cases. Patients who received lot numbers
CA5410A,
CA5412A, CA5413A, or CA5421A of AlphaNine S-D (TM) since July 1,
1995,
should be tested for IgM anti-HAV. Patients receiving any clotting
factor
who develop symptoms of acute hepatitis should have a complete
diagnostic
evaluation, including testing for IgM anti-HAV. A positive test for
IgM
anti-HAV is evidence of HAV infection during the previous 6 months.
Persons
who are anti-HAV positive and IgM anti-HAV negative had HAV
infection
greater than 6 months previously and are immune. Patients who are
IgM
anti-HAV positive should be reported to their local or state health
department and directly to CDC's Hematologic Disease Branch, Div of
AIDS,
STD, and TB Laboratory Research, National Center for Infectious
Diseases
(NCID), telephone (404) 639-3925.

Inactivated hepatitis A vaccine (HAVRIX {Registered},
SmithKline
Beecham, Inc., Pittsburgh, Pennsylvania) was licensed in 1995, and
physicians should consider vaccinating susceptible patients who
receive
clotting factor. Because limited available data suggest a high
seroprevalence of anti-HAV among persons with hemophilia, all such
patients
should undergo prevaccination testing. Persons who are anti-HAV
(total)
positive are immune to HAV and do not require vaccination. The
vaccine
provides active immunity against HAV, which is estimated to persist
for at
least 20 years in healthy adults (10). Information about the
vaccine's
effectiveness in persons with hemophilia and immunocompromised
persons is
limited. The vaccine is licensed as a two-dose series of 1440 ELISA
units
(EL.U.) per dose for adults, with the second dose administered 6-12
months
after the first dose, and in a 3-dose series of 360 EL.U. per dose
for
children aged 2-18 years, with the second dose administered 1 month
after
the first dose, and the third dose administered 6-12 months after
the first
dose. The vaccine is not licensed for use in children aged less
than 2
years. The vaccine should be administered by intramuscular
injection in the
deltoid. A physician familiar with the patient's risk for bleeding
should
evaluate whether the vaccine can be given with reasonable safety by
this
route. No data are available regarding administration of the
vaccine by the
intradermal or subcutaneous route. If the patient receives clotting
factor
or other similar therapy, intramuscular vaccination can be
scheduled
shortly after receipt of such therapy.

Patients should consult their physician or health-care
provider for
answers to any questions related to their current factor VIII or
factor IX
replacement product. Additional information about this
investigation is
available from the Hematologic Diseases Branch and additional
information
about the hepatitis A vaccine, including preventive measures for
children
aged less than 2 years, is available from CDC's Hepatitis Branch,
Division
of Viral and Rickettsial Diseases, NCID, telephone (404) 639-3048.

Use of trade names and commercial sources is for identification
only and
does not imply endorsement by the Public Health Service or the U.S.
Department of Health and Human Services.

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